This SBIR Fast-Track proposal meets the objectives of NHLBI Small Business Topic of Special Interest for Fiscal Year 2017 Code HLS17-04. Myelodysplastic syndromes (MDS) are genetically and morphologically diverse hematopoietic neoplasms that arise from a small pool of mutant clones within hematopoietic stem and progenitor compartments. Only three drugs have received regulatory approval specifically for MDS treatment, all with suboptimal response rates of <50% and of limited durability, typically 1-2 years. Once these agents are no longer effective, there is no standard of care established for second-line treatment (i.e., in the relapsed/refractory setting). Furthermore, prognosis after hypomethylating agent failure is dismal, with median survival estimated at <6 months for higher-risk patients, and <18 months for lower-risk patients. Clearly there is a significant unmet need for a new MDS treatment that both (a) eradicates preleukemic stem cells and leads to long-term remission and normalization of cytopenias, and (b) achieves this goal without the heavy cost of side effects, particularly in lower-risk MDS. Stem cells and early progenitors from MDS patients consistently overexpressed the chemokine CXCL8 (IL-8) and its receptor, CXCR2. Inhibition of CXCR2 selectively arrested the growth of stem cells from MDS patients but not healthy controls, demonstrating preclinical therapeutic proof-of-principle and validating CXCR2 as a therapeutic target in MDS. Additionally, myeloid-derived suppressor cells (MDSCs) are markedly increased in the bone marrow of MDS patients where they induce myelodysplasia and impair immune surveillance and clearance of mutant clones. CXCR2 and CXCR1 are pivotal in MDSC recruitment. Dual CXCR1 and CXCR2 (CXCR1/2) inhibition is therefore a novel therapeutic strategy to treat MDS with a ?one- two punch? to (i) the mutant MDS cells directly and (ii) the MDSC-driven immunosuppressive marrow microenvironment. Developed by Syntrix in a decade's long discovery effort supported by NHLBI (IND open for melanoma 4/16), SX-682 is a new-in-class oral, small-molecule, immuno-oncology (IO) therapy directed at disrupting CXCR1/2 signaling. We hypothesize that in MDS, SX-682 will lead to long-term remissions and normalization of cytopenias, but with only a mild side-effect effect profile compared to other therapies. If successful, SX-682 would revolutionize the existing treatment landscape in MDS. Through execution of the Specific Aims, we will advance SX-682 through a Phase 1, open label dose-escalation and expansion trial to evaluate SX-682 in MDS patients who had progression or were intolerant to prior therapy. The SX-682 MDS IND 131,876 was opened on September 1, 2017, and enrollment for this trial may begin.